Terbinafine, chemically defined as (E)-N-(6,6-dimethyl-2-hepten-4-inyl)-N-methyl-1-naphthalene-methylamine and having the structure (1), is an antimicotic drug for topical and oral use, having the following chemical structure:

The first, laboratory scale, synthetic route for this compound is described in European patent EP 0 024 587 and consists in reacting the lithium salt of tert-butylacetylene with acrolein, followed by an allylic bromination/rearrangement reaction, to give the intermediate (E+Z)-1-bromo-6,6-dimethyl-hepten-4-ine, which is then condensed with (1-naphthylmethyl)methylamine to give a mixture of (E+Z)-N-(6,6-dimethyl-2-hepten-4-inyl)-N-methyl-1-naphthalene-methylamine from which terbinafine (1) is then isolated, in the hydrochloride form. This synthetic route has several drawbacks if used on the industrial scale; firstly, the use of acrolein, a toxic substance, difficult to obtain and transport in moderate industrial amounts and, above all, in the final stage, the formation of a mixture of E+Z isomers which must be separated by crystallisation, thus leading to a drastic reduction in the process yield.
More recently, various alternative synthetic routes have been identified, leading to more industrially convenient processes. For example, the article by Alami et al., Tetrahedron Lett., 37, 57-58, (1996) describes the following synthetic method:

This process comprises the initial alkylation of (1-naphthylmethyl)methanamine (2), with 1,3-dichloropropene (3), raw materials which are both commercially available, to give the intermediate N-(3-chloro-2-propenyl)-N-methyl-1-naphthalene-methylamine (4).
This latter intermediate undergoes a “Heck-coupling” type reaction with tert-butylacetylene (5) in the presence of palladium or copper catalysts, to give terbinafine (1). Essentially analogous processes are described in patents EP 0 421 302 and EP 0 645 369 and in the recent patent applications WO 01/77064, WO 02/02503 and EP 1 236 709. The latter report novel processes for final coupling using other types of catalysts, or particular reaction conditions. This synthetic route is brief, simply executed and generally characterised by good overall yield. On the other hand, it has low industrial applicability since it uses tert-butylacetylene (5), a reagent that is still rather costly, together with palladium complexes and/or salts (for example tetrakis(triphenylphosphine)palladium(0) or dichloro-bis(triphenylphosphine)palladium(II)), themselves also rather expensive. This has an influence over the final cost of the drug, with obvious social consequences.